BYLVAY Hard capsule Ref.[27935] Active ingredients: Odevixibat

The mechanism of action of odevixibat requires that the enterohepatic circulation of bile acids and bile salt transport into biliary canaliculi is preserved. Conditions, medications or surgical procedures that impair either gastrointestinal motility, or enterohepatic circulation of bile acids, including bile salt transport to biliary canaliculi have the potential to reduce the efficacy of odevixibat. For this reason, e.g. patients with PFIC2 who have a complete absence or lack of function of Bile Salt Export Pump (BSEP) protein (i.e. patients with BSEP3 subtype of PFIC2) will not respond to odevixibat.

There are limited or no clinical data with odevixibat in PFIC subtypes other than 1 and 2.

Patients with severe hepatic impairment (Child-Pugh C) have not been studied (see section 5.2). Periodic liver function tests should be considered for patients with severe hepatic impairment.

Diarrhoea has been reported as a common adverse reaction when taking odevixibat. Diarrhoea may lead to dehydration. Patients should be monitored regularly to ensure adequate hydration during episodes of diarrhoea (see section 4.8).

In clinical trials, increased levels in liver function tests were observed in some patients receiving odevixibat. Assessment of liver function tests (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase and total bilirubin) is recommended for all patients prior to initiating Bylvay, with monitoring per standard clinical practice.

For patients with liver function test elevations, more frequent monitoring should be considered.

Assessment of fat-soluble vitamin levels (Vitamins A, D, E) and international normalised ratio (INR) are recommended for all patients prior to initiating Bylvay, with monitoring per standard clinical practice.

Treatment with odevixibat may impact the absorption of fat-soluble medicinal products, including lipophilic oral contraceptives (see sections 4.5 and 4.6).

Transporter-mediated interactions

Odevixibat is a substrate for the efflux transporter P-glycoprotein (P-gp). In adult healthy subjects, co-administration of the strong P-gp inhibitor itraconazole increased the plasma exposure of a single dose of odevixibat 7 200 mcg by approximately 50-60%. This increase is not considered clinically relevant. No other potentially relevant transporter-mediated interactions were identified in vitro (see section 5.2).

Cytochrome P450-mediated interactions

In vitro, odevixibat did not induce CYP enzymes (see section 5.2).

In in vitro studies, odevixibat was shown to be an inhibitor of CYP3A4/5 (see section 5.2).

In adult healthy subjects, concomitant use of odevixibat decreased the area under the curve (AUC) of oral midazolam (a CYP3A4 substrate) by 30% and 1-OH-midazolam exposure by less than 20%, which is not considered clinically relevant.

No interaction studies have been conducted with UDCA and rifampicin.

In an interaction study with a lipophilic combination oral contraceptive containing ethinyl estradiol (EE) (0.03 mg) and levonorgestrel (LVN) (0.15 mg) conducted in adult healthy females, concomitant use of odevixibat had no impact on the AUC of LVN and decreased the AUC of EE by 17%, which is not considered clinically relevant. Interaction studies with other lipophilic medicinal products have not been performed, therefore, an effect on the absorption of other fat-soluble medicinal products cannot be excluded.

In clinical trials, decreased levels of fat-soluble vitamins were observed in some patients receiving odevixibat. Levels of fat-soluble vitamins should be monitored (see section 4.4).

Paediatric population

No interaction studies have been performed in paediatric patients. No differences are expected between the adult and paediatric populations.

Women of childbearing potential

Women of childbearing potential should use an effective method of contraception when treated with Bylvay.

Pregnancy

There are no or limited data from the use of odevixibat in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). Bylvay is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether odevixibat or its metabolites are excreted in human milk. There is insufficient information on the excretion of odevixibat in animal milk (see section 5.3).

A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Bylvay therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

No fertility data are available in humans. Animal studies do not indicate any direct or indirect effects on fertility or reproduction (see section 5.3).

Bylvay has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most commonly reported adverse reaction was diarrhoea reported in (7%) of patients.

Tabulated list of adverse reactions

The table lists adverse reactions identified in clinical trials in patients with PFIC aged between 4 months to 25 years of age (median 3 years 7 months).

Adverse reactions are ranked according to system organ class, using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000) and not known (cannot be estimated from the available data).

Table 3. Frequency of adverse reactions in PFIC patients:

^a Includes abdominal pain upper

Description of selected adverse reactions

Gastrointestinal adverse reactions

Gastrointestinal adverse reactions occurred at a frequency of 11% in patients treated with Bylvay. Adverse reactions of diarrhoea, abdominal pain and faeces soft were of short duration with most events ≤5 days in duration; median time to first onset was 16 days. All reports were mild to moderate in severity and non-serious. Two patients experienced an adverse reaction of clinically significant diarrhoea defined as diarrhoea that persisted for 21 or more days without any other aetiology, was severe in intensity, required hospitalisation or was considered an important medical event, or presented with concurrent dehydration requiring treatment with oral or intravenous rehydration and/or other treatment intervention (see section 4.4). Treatment interruption was reported for diarrhoea in 4% of patients and discontinuation of Bylvay due to diarrhoea was reported in 1%.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.